A direct synthesis of oxazoles from aldehydes

Article abstract of DOI:10.1021/ol101346w

An expedient method for the direct conversion of aldehydes to 2,4-disubstituted oxazoles is presented. The method relies on the oxidation of an oxazolidine formed from the condensation of serine with an aldehyde and proceeds through a 2,5-dihydrooxazole intermediate. In contrast to standard methods that start from carboxylic acids, the use of aldehydes as starting materials does not require intermediate purification and affords the oxazoles under relatively mild conditions.

Full text of DOI:10.1021/ol101346w

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3614-3617
A Direct Synthesis of Oxazoles from
Aldehydes
Thomas H. Graham
Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065-0900
thomas.graham@merck.com
Received June 11, 2010
ABSTRACT
An expedient method for the direct conversion of aldehydes to 2,4-disubstituted oxazoles is presented. The method relies on the oxidation of
an oxazolidine formed from the condensation of serine with an aldehyde and proceeds through a 2,5-dihydrooxazole intermediate. In contrast
to standard methods that start from carboxylic acids, the use of aldehydes as starting materials does not require intermediate purification and
affords the oxazoles under relatively mild conditions.
Efficiency is a perennial topic in organic synthesis, and the
concept is described by numerous terms including atom
economy,1 step economy,2 the Taxol problem,3 and the
arithmetic demon.4 The concept of efficiency impacts modern
pharmaceutical research when aggressive research timelines
require rapid access to privileged pharmacophores.5 With
the goal of developing more efficient and expedient routes
to important heterocycles, the synthesis of 2,4-disubstituted
oxazoles was re-examined.
Oxazoles are a common structural motif found in numer-
ous molecules that display antiviral, antifungal, antibacterial,
and antiproliferative activities.6 The potent biological activity
and the prevalence of oxazoles in both natural products and
pharmaceuticals has inspired significant interest in the
synthesis of these heterocycles.7
cyclization of serine-containing peptides.8 Similarly, a com-
mon route for the synthesis of 2,4-disubstituted oxazoles
relies on carboxylic acids and amino-alcohols as starting
materials (Figure 1). Specifically, the coupling of a carboxylic
acid with a suitable amino-alcohol followed by a dehydrative
cyclization affords 2-oxazolines,9 which are then oxidized10
to afford the oxazole (1) (Figure 1, Path I). Alternatively,
the oxidation step can precede the cyclization step, affording
an oxo-amide intermediate, which upon dehydrative cycliza-
tion affords 1 (Figure 1, Path II).11 Although these methods
(6) (a) Oxazoles: Synthesis, Reactions and Spectroscopy, Part A; Palmer,
D. C., Ed.; John Wiley & Sons: Hoboken, NJ, 2003. (b) Oxazoles: Synthesis,
Reactions and Spectroscopy, Part B; Palmer, D. C., Ed.; John Wiley &
Sons: Hoboken, NJ, 2004.
(7) (a) Jin, Z. Nat. Prod. Rep. 2006, 23, 464. (b) Yeh, V. S. C.
Tetrahedron 2004, 60, 11995. (c) Wipf, P. Chem. ReV. 1995, 95, 2115.
(8) (a) Walsh, C. T. Science 2004, 303, 1805. (b) Li, Y.-M.; Milne,
J. C.; Madison, L. L.; Kolter, R.; Walsh, C. T. Science 1996, 274, 1188.
(9) (a) Li, Z.; Xu, Q. Tetrahedron Lett. 2009, 50, 6838. (b) Sakakura,
A.; Kondo, R.; Ishihara, K. Org. Lett. 2005, 7, 1971. (c) Wuts, P. G. M.;
Northuis, J. M.; Kwan, T. A. J. Org. Chem. 2000, 65, 9223. (d) Phillips,
A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2,
1165. (e) Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679. (f)
Lafargue, P.; Guenot, P.; Lellouche, J.-P. Heterocycles 1995, 41, 947. (g)
Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267. (h) Wipf, P.; Miller,
C. P. Tetrahedron Lett. 1992, 33, 907. (i) Gale´otti, N.; Montagne, C.; Poncet,
J.; Jouin, P. Tetrahedron Lett. 1992, 33, 2807. (j) Burrell, G.; Evans, J. M.;
Jones, G. E.; Stemp, G. Tetrahedron Lett. 1990, 31, 3649. (k) Vorbru¨ggen,
H.; Krolikiewicz, K. Tetrahedron Lett. 1981, 22, 4471.
2,4-Disubstituted oxazoles are incorporated into natural
products by the nonribosomal peptide synthase mediated
(1) Trost, B. M. Science 1991, 254, 1471.
(2) Wender, P. A.; Croatt, M. P.; Witulski, B. Tetrahedron 2006, 62,
7505.
(3) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477.
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NJ, 1969.
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10.1021/ol101346w  2010 American Chemical Society
Published on Web 07/19/2010

are common in modern organic synthesis, they often require
intermediate purifications and moisture-sensitive reagents,
which can limit the overall efficiency and utility of the
process.
reaction conditions, or noncommercial starting materials, and
these factors can limit the scope and utility of the transfor-
mations. Considering the potential efficiency of the process,
a more mild method for the direct conversion of aldehydes
to oxazoles was envisioned.
Figure 1. Common synthetic routes for accessing oxazoles from
carboxylic acids: (a) amide coupling, (b) dehydrative cyclization,
and (c) oxidation.
Figure 2. Proposed reaction pathway for the conversion of
aldehydes to oxazoles.
An alternative method for the preparation of oxazoles
begins with aldehydes rather than carboxylic acids. Several
methods for the conversion of aldehydes to oxazoles have
been reported. Badr and co-workers demonstrated the
transformation via an oxazolidine intermediate, formed by
the condensation of an aromatic aldehyde with serine.12 The
two-step method uses N-bromosuccinimide in refluxing CCl4
to oxidize the oxazolidines to 2-aryl oxazoles. In another
method, the condensation of aldehydes and R-keto-oximes
in HCl and acetic acid affords oxazole-N-oxides, which are
subsequently reduced to afford the desired oxazoles.13 A third
method involves the condensation of an aldehyde with an
R-amino-ketone, followed by a subsequent oxidation to give
the oxazole.14 These methods require multiple steps, harsh
The conversion of aldehydes to oxazoles discussed in this
communication is based on the mechanistic hypothesis shown
in Figure 2. The condensation of an aldehyde with an amino-
alcohol yields the oxazolidine, which is reported to exist as
a solvent-dependent equilibrium mixture of ring-chain
tautomers 2a and 2b.15 Oxidation of the oxazolidine affords
the intermediate 2,5-dihydrooxazole 3,16,17 which isomerizes
under the reaction conditions to give oxazoline 4.18 A second
oxidation affords oxazole 1. The BrCCl3/ DBU system,
originally developed by Williams and co-workers,10c was
employed to oxidize the oxazolidine to the oxazole while
also providing conditions to effect the required 1,3-isomer-
ization.19,20
Initial studies focused on a two-step protocol to better
understand the requirements for the transformation (Table
(10) (a) Yamamoto, K.; Chen, Y. G.; Buono, F. G. Org. Lett. 2005, 7,
4673. (b) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai,
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P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett. 1997, 38, 331. (d) Tavares,
F.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 6803. (e) Barrish, J. C.; Singh,
J.; Spergel, S. H.; Han, W.-C.; Kissick, T. P.; Kronenthal, D. R.; Mueller,
R. H. J. Org. Chem. 1993, 58, 4494. (f) McGarvey, G. J.; Wilson, K. J.;
Shanholtz, C. E. Tetrahedron Lett. 1992, 33, 2641. (g) Evans, D. L.; Minster,
D. K.; Jordis, U.; Hecht, S. M.; Mazzu, A. L., Jr.; Meyers, A. I. J. Org.
Chem. 1979, 44, 497.
(15) (a) La´za´r, L.; Fu¨lo¨p, F. Eur. J. Org. Chem. 2003, 3025. (b) Fu¨lo¨p,
F.; Pihlaja, K. Tetrahedron 1993, 49, 6701.
(16) (a) Johannes, K.; Jakob, J.; Hatam, M.; Martens, J. Synthesis 2009,
3279. (b) Chakraborty, R.; Franz, V.; Bez, G.; Vasadia, D.; Popuri, C.;
Zhao, C.-G. Org. Lett. 2005, 7, 4145. (c) Favreau, S.; Lizzani-Cuvelier,
L.; Loiseau, M.; Dun˜ach, E.; Fellous, R. Tetrahedron Lett. 2000, 41, 9787.
(d) Sa´, M. C. M.; Kascheres, A. J. Org. Chem. 1996, 61, 3749. (e) Do¨mling,
A.; Bayler, A.; Ugi, I. Tetrahedron 1995, 51, 755. (f) Hua, D. H.; Khiar,
(11) (a) Wipf, P.; Graham, T. H. J. Org. Chem. 2001, 66, 3242. (b)
Wipf, P.; Lim, S. Chimia 1996, 50, 157. (c) Wipf, P.; Lim, S. J. Am. Chem.
Soc. 1995, 117, 558. (d) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58,
3604.
N.; Zhang, F.; Lambs, L. Tetrahedron Lett. 1992, 33, 7751.
(17) Alternatively, bromination of the open-chain form followed by SN2′
cyclization would also afford the 2,5-dihydrooxazole intermediate, although
both cyclizations contradict Baldwin’s suggestions: Baldwin, J. E. J. Chem.
(12) Badr, M. Z. A.; Aly, M. M.; Fahmy, A. M.; Mansour, M. E. Y.
Bull. Chem. Soc. Jpn. 1981, 54, 1844.
Soc., Chem. Commun. 1976, 734.
(18) For additional examples of oxidation-state transfer by isomerization
in oxazoline systems, refer to: (a) Williams, D. R.; Berliner, M. A.; Stroup,
B. W.; Nag, P. P.; Clark, M. P. Org. Lett. 2005, 7, 4099. (b) Hermitage,
S. A.; Cardwell, K. S.; Chapman, T.; Cooke, J. W. B.; Newton, R. Org.
Process Res. DeV. 2001, 5, 37. (c) Cardwell, K. S.; Hermitage, S. A.; Sjolin,
A. Tetrahedron Lett. 2000, 41, 4239.
(13) (a) Cai, X.-H.; Yang, H.-J.; Zhang, G.-L. Synthesis 2005, 1569.
(b) Weintraub, P. M. J. Med. Chem. 1972, 15, 419. (c) Goto, Y.; Yamazaki,
M.; Hamana, M. Chem. Pharm. Bull. 1971, 19, 2050. (d) Allan, A. W.;
Walter, B. H. J. Chem Soc. C. 1968, 1397. (e) Bodendorf, K.; Towliati, H.
Arch. Pharm. 1965, 298, 293. (f) Selwitz, C. M.; Kosak, A. I. J. Am. Chem.
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1947, 96. (h) von Dilthey, W.; Friedrichsen, J. J. Prakt. Chem. 1930, 127,
292. (i) Diels, O.; Riley, D. Ber. 1915, 48, 897.
(19) For the conversion of oxazolidines to 2-oxazolines, refer to: (a)
Takahashi, S.; Togo, H. Synthesis 2009, 2329. (b) Schwekendiek, K.;
Glorius, F. Synthesis 2006, 2996. (c) Sayama, S. Synlett 2006, 1479
.
(14) (a) Colotta, V.; Catarzi, D.; Varano, F.; Cecchi, L.; Filacchioni,
G.; Martini, C.; Giusti, L.; Lucacchini, A. Il Farmaco 1998, 53, 375. (b)
Merchant, J. R.; Desai, H. K. Indian J. Chem. 1973, 11, 433.
(20) For the preparation of thiazoles from aldehydes, refer to: Fernandez,
X.; Fellous, R.; Lizzani-Cuvelier, L.; Loiseau, M.; Dun˜ach, E. Tetrahedron
Lett. 2001, 42, 1519
.
Org. Lett., Vol. 12, No. 16, 2010
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methylene chloride resulted in a 12% yield of 6 (Table 2,
entry 3). The use of DMA as a solvent and potassium
carbonate or potassium phosphate as a base provided
complete conversion to 6 in 79% yield (Table 2, entries 4
and 5).
Table 1. Optimizing the Conversion of 5a/b to Oxazole 6
Table 2. Optimizing the One-Pot Synthesis of Oxazole 6
BrCCl3
equiv
DBU
equiv
yield (%)c
entry
solvent
ratio 6:7
yield (%)b
entry
additive
solvent
ratio 6:7
48c
69
70
73
79
1
2
3
4
5
Et3N (1 equiv)b
Et3N (1 equiv)b
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K3PO4 (1 equiv)
CH2Cl2
DMA
CH2Cl2
DMA
4:1
7:1
1:0
1:0
1:0
71
81
12
79
79
1
2
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMA
1
2
2.5
3
3
1
2
2.5
3
3
1:2
4:1
20:1
1:0
1:0
DMA
a Reaction conditions: BrCCl3, DBU, 0 °C to rt, 12 h. b Yields were
determined after purification by column chromatography on silica gel.
c 2-Phenyloxazoline-4-carboxylic acid methyl ester was isolated in 10%
yield.
a Reaction conditions: Ser-OMe·HCl (1 equiv), additive, rt, 12 h, then
BrCCl3 (3 equiv), DBU (3 equiv), 0 °C to rt, 12 h. b With MgSO4 (1 equiv).
c Yields were determined after purification by column chromatography on
silica gel.
1). The model oxazolidine was prepared from benzaldehyde
and serine methyl ester hydrochloride using literature meth-
ods.15 The oxazolidine was isolated in quantitative yield and
high purity after a simple filtration to remove the Et3N·HCl
and MgSO4. The oxidation of the oxazolidine was initially
studied with variable amounts of BrCCl3 and DBU in
methylene chloride. With 1 equiv each of BrCCl3 and DBU,
an inseparable mixture of oxazole 69d and 2,5-dihydrooxazole
7 was isolated in a 1:2 ratio and 48% combined yield (Table
1, entry 1). The known 2-phenyloxazoline-4-carboxylic acid
methyl ester,21 corresponding to intermediate 4 in Figure 2,
was also isolated in 10% yield. The presence of 7 and the
2-oxazoline, suggests the mechanism outlined in Figure 2 is
operating. The use of 3 equiv each of BrCCl3 and DBU was
required to completely convert 5a/b to 6 in 73% yield (Table
1, entry 4).
A solvent evaluation indicated that the use of a polar
aprotic solvent such as N,N-dimethylacetamide (DMA)
afforded 6 in 79% yield (Table 1, entry 5). The efficiency
of the reaction in DMA is an interesting result considering
that, in polar aprotic solvents, the ring-chain tautomer
equilibrium of 5a and 5b is shifted almost exclusively toward
the open form (5b).15
With the two efficient methods for the direct conversion
of aldehydes to oxazoles, the scope of the transformation
was studied (Table 3). Halogen-substituted benzaldehydes
performed similarly to the parent benzaldehyde, affording
the corresponding oxazoles in good yields for both the two-
step (condition A) and the one-pot (condition B) procedures
(Table 3, entries 1-3). In addition, both electron-poor (Table
3, entries 4 and 5) and electron-rich benzaldehydes (Table
3, entry 6) afforded the corresponding oxazoles. The method
was also extended to heteroaromatic systems. Pyridines,
quinolines, furans, and thiophenes (Table 3, entries 7-12)
were tolerated by the reaction conditions.
A further extension of the method affords 2-alkenyl and
2-alkynyl oxazoles. Cinnamaldehyde and R-methyl cinna-
maldehyde afforded the corresponding oxazole in 72% and
70% yield, respectively, using the two-step procedure (Table
4, entries 1 and 2). 2,4-Hexadienal afforded the correspond-
ing 2-pentadienyl oxazole in 60% yield (Table 4, entry 3).
In contrast, 2-hexenal afforded the 2-pentenyl oxazole in 28%
yield (Table 4, entry 4). 2-Alkynyl aldehydes also afforded
the corresponding 2-alkynyl oxazoles (Table 4, entries 5 and
6). Attempts to use the one-pot method (i.e., Table 3,
condition B) for any of the substrates in Table 4 resulted in
a progressive darkening of the reaction mixtures from which
only traces of the intended products were obtained.22
In conclusion, an efficient method for the expedient
synthesis of 2,4-disubstituted oxazoles from aldehydes is
described. The method relies on the oxidation of an oxazo-
lidine formed from the condensation of serine with an
aldehyde and proceeds through a 2,5-dihydrooxazole inter-
With the feasability of the transformation established, the
one-pot conversion of an aldehyde to an oxazole was
attempted (Table 2). Stirring serine methyl ester hydrochlo-
ride and benzaldehyde with triethylamine and magnesium
sulfate in either methylene chloride or DMA for 12 h at
ambient temperature followed by the addition of BrCCl3 and
DBU at 0 °C afforded inseparable mixtures of the desired
oxazole 6 and the intermediate 2,5-dihydrooxazole 7 (Table
2, entries 1 and 2). The use of potassium carbonate in
(22) Attempts to prepare a representative 2-alkyloxazole using hydro-
cinnamaldehyde under conditions A or B afforded a complex mixture of
the intended 2-phenethyloxazole, the intermediate 2-phenethyl-2,5-dihy-
drooxazole, and other unidentified byproducts.
(21) Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141.
3616
Org. Lett., Vol. 12, No. 16, 2010

Table 3. Preparation of 2-Aryl and 2-Heteroaryl Oxazoles from
Aldehydes
Table 4. Preparation of 2-Alkenyl and 2-Alkynyl Oxazoles from
Aldehydes
a Condition A: (i) Ser-OMe·HCl (1 equiv), Et3N (2 equiv), MgSO4 (1
equiv), THF, rt, 12 h, then filter; (ii) BrCCl3 (3 equiv), DBU (3 equiv),
CH2Cl2, 0 °C to rt, 12 h. b Yields were determined after purification by
column chromatography on silica gel.
mediate. In contrast to other procedures, the method utilizes
readily available aldehydes, does not require intermediate
purification, and affords the oxazoles under relatively mild
conditions. Furthermore, the results demonstrate how the
careful consideration of potential reactivities can lead to a
more efficient and expedient synthesis of an important
heterocyclic system.
Acknowledgment. The author acknowledges Merck Re-
search Laboratories for supporting this research. Charles Ross
(MRL West Point) is acknowledged for the acquisition of
high resolution mass spectrometry data.
a Yields were determined after purification by column chromatography
on silica gel. b Condition A: (i) Ser-OMe·HCl (1 equiv), Et3N (2 equiv),
MgSO4 (1 equiv), THF, rt, 12 h, then filter; (ii) BrCCl3 (3 equiv), DBU (3
equiv), CH2Cl2, 0 °C to rt, 12 h. Condition B: Ser-OMe·HCl (1 equiv),
K2CO3 (2 equiv), DMA, rt, 12 h, then BrCCl3 (3 equiv), DBU (3 equiv), 0
°C to rt, 12 h.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101346W
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